The natural history of mammary tumorigenesis is characterized by the progressive selection and outgrowth of mutant clones of cells that possess increasingly aggressive properties. Although this process is ultimately responsible for cancer mortality, the molecular and cellular alterations that underlie breast cancer progression are largely unknown. As such, elucidating the molecular pathways that are involved in tumor progression is a critical priority in breast cancer research. Such pathways undoubtedly regulate proliferation, survival, differentiation, and local invasion, as well as multiple other properties of epithelial and stromal cells within the mammary gland. Amplification of the proto-oncogene, c-MYC, occurs in a subset of human breast cancers and is associated with aggressive tumor behavior and poor prognosis. Although c-MYC has been shown to affect cellular proliferation, differentiation, and apoptosis, the genetic mechanisms responsible for the aggressive behavior of c-MYC amplified tumors is unknown. To better define the role played by c-MYC in the multistep processes of mammary carcinogenesis and breast cancer progression we have created a novel bitransgenic murine model system in which c-MYC can be inducibly expressed in the mammary epithelium of animals treated with tetracycline derivatives. This model system permits the direct visualization and analysis of each stage of tumorigenesis from normal mammary tissue in the uninduced state to invasive adenocarcinomas that arise as a consequence of c-MYC overexpression. Remarkably, many of these invasive tumors regress to a clinically undetectable state following deinduction of the c-MYC transgene. Moreover, nearly half of c-MYC-induced mammary adenocarcinomas harbor spontaneous activating point mutations in the ras family of proto-oncogenes, with a strong preference for K-ras compared to H-ras. Surprisingly, we have found that nearly all tumors lacking activating ras mutations fully regress following deinduction of MYC transgene expression, whereas tumors bearing ras mutations do not. Our findings indicate that c-MYC-induced mammary tumorigenesis proceeds via a preferred secondary oncogenic pathway involving K-ras, and suggest a role for K-ras in the progression of c-MYC-induced breast cancers. We believe that the model system that we have created presents a valuable new opportunity for studying the molecular events that contribute to tumor progression. In particular, defining a role for K-ras, or molecules induced by K-ras, in the progression of c-MYC-induced breast cancer would contribute to our understanding of the biological basis for the aggressive behavior of this subset of human breast cancers. Ultimately, elucidating the broad range of molecular alterations that occur during breast cancer progression will facilitate the development of chemotherapeutic agents tailored to the more aggressive forms of this disease.